The references cited herein are not admitted to be prior art to the claimed invention.
Neuropeptides present in the hypothalamus play a major role in mediating the control of body weight. (Flier et al., 1998, Cell, 92, 437–440.) Melanin-concentrating hormone (MCH) is a cyclic 19-amino acid neuropeptide synthesized as part of a larger pre-prohormone precursor in the hypothalamus that also encodes neuropeptides NEI and NGE. (Nahon et al., 1990, Mol. Endocrinol., 4, 632–637.) MCH was first identified in salmon pituitary, and in fish MCH affects melanin aggregation thus affecting skin pigmentation. In trout and in eels MCH has also been shown to be involved in stress induced or CRF-stimulated ACTH release. (Kawauchi et al., 1983, Nature, 305, 321–323.)
In humans two genes encoding MCH have been identified that are expressed in the brain. (Breton et al., 1993, Mol. Brain Res., 18, 297–310.) In mammals MCH has been localized primarily to neuronal cell bodies of the hypothalamus which are implicated in the control of food intake, including perikarya of the lateral hypothalamus and zona inertia. (Knigge et al., 1996, Peptides, 17, 1063–1073.)
Pharmacological and genetic evidence suggest that the primary mode of MCH action is to promote feeding (orexigenic). MCH mRNA is up regulated in fasted mice and rats and in the ob/ob mouse. (Qu et al., 1996, Nature, 380, 243–247.) Injection of MCH centrally (ICV) stimulates food intake and MCH antagonizes the hypophagic effects seen with α-melanocyte stimulating hormone (αMSH). (Qu et al., 1996, Nature, 380, 243–247.) MCH-deficient mice are lean, hypophagic, and have increased metabolic rate. (Shimada et al., 1998, Nature, 396, 670–673.)
MCH action is not limited to modulation of food intake as effects on the hypothalamic-pituitary-axis have been reported. (Nahon, 1994, Critical Rev. in Neurobiol., 8, 221–262.) MCH may be involved in the body response to stress as MCH can modulate the stress-induced release of CRF from the hypothalamus and ACTH from the pituitary. In addition, MCH neuronal systems may be involved in reproductive or maternal function.
Several references describe a receptor that is indicated to bind MCH. (Chambers et al., 1999, Nature, 400, 261–265; Saito et al., 1999, Nature, 400, 265–269; Bächner et al., 1999, FEBS Letters, 457, 522–524; Shimomura et al., 1999, Biochemical and Biophysical Research Communications, 261, 622–626; and Lembo et al., 1999, Nat. Cell Biol., 1, 267–271.)